Dysfunction of the basal ganglia plays a critical role in the pathogenesis of Parkinson's disease, Huntington's disease and dystonia. There is evidence that NMDA and dopaminergic receptors contribute to neurodegenerative and/or regulatory processes that contribute to underly these diseases. One population of cells that has a central position in movement disorders is the medium-sized spiny neuron (MSN) of the neostriatum; this neuron has a direct role in integrating motor circuits of the basal ganglia, including cortical (NMDA) and nigral (dopaminergic) inputs. There is virtually no information on the cellular bases or mechanisms by which these afferents interact, yet understanding how the MSN uses information dependent on NMDA and dopaminergic receptors is essential to our long-term objective of unlocking mechanisms of basal ganglia disorders. The proposed experiments, based on studies from this and many other laboratories, test the hypothesis that NMDA (NMDAR) and dopaminergic receptors in the MSN activate signaling circuits that converge to alter the expression of AP-1 ( Fos:Jun) DNA binding proteins. Three aims are put forth. Aim 1 determines whether the extent of coexpression of NMDA and dopamine (D1 or D2) coupled receptors in the same MSN, to establish anatomic support for their convergence. Aim 2 tests the hypothesis that both NMDAR and dopaminergic activation converge on the Ca++/CRE(Ca++ and cAMP mediated) transcription site on the promoter of the c-fos gene. Aim 3 identifies the proteins interacting with AP-1 transcription sites, in three genes in the neostriatum putatively regulated by NMDA and dopamine activation: c-fos, preprotachykinin and preproenkephalin A. These experiments in the rat neostriatum are designed to elucidate pathways in the MSN, by which receptor activation leads to gene transcription. The c-fos gene encodes a candidate transcription factor in the neostriatum regulatable by dopamine and NMDA. The two peptide genes encode neuropeptide transmitters specific to the MSN in the neostriatum; both have AP-1 sites on their promoters. These aims will be studies using a multidisciplinary approach; in situ hybridization and immunohistochemistry (light and electron microscopy) in aim 1, and gel mobility shift assay, methylation interference assay, DNA-affinity chromatography and Western blot analysis in aims 2 and 3. The advantage of using these complementary strategies is that receptor localization at the cellular level can be interpreted in conjunction with the identification of proteins binding to gene transcription sties at the molecular level. The excitement of studying the control and activity of transcription factors is that they may have critical roles in adaptive regulatory changes in Parkinson's disease, Huntington's disease and dystonia.